Peroxisome proliferators (PPs) are a class of agents that are ubiquitous in the environment and are categorized as high-volume production chemicals. Many of these agents are very potent rodent liver carcinogens but it is not clear whether they are carcinogenic to humans. The mechanism of action of PPs is non-genotoxic and involves increases in peroxisomal activity and cell proliferation in liver. While PPs have been studied extensively, uncertainty remains regarding the exact mechanism and the basis for species differences. Two key players in the mode of action of these agents are nuclear receptor PPAR-alpha in parenchymal cells, known to be required for liver cancer in rodents, and TNF-alpha, a mitogenic cytokine in Kupffer cells that induces cell proliferation. The goal of this research is to develop a better understanding of the molecular pathways by which PPAR-alpha and TNF-alpha are involved in rodent tumorigenesis. We hypothesize that PPs cause increased oxidant production in Kupffer cells, which signal activation of TNF-alpha and other mitogenic cytokines that require PPAR-alpha for rapid hepatic cell proliferation. The findings of this research will help in assessing human risk to these and perhaps other non-genotoxic carcinogens.